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Antibiotics, Lung Cancer, Dying of a Broken Heart, Gender Bias

Margaret McCartney unpicks recent headlines suggesting its okay not to finish your antibiotics. Plus lung cancer screening in the high risk and can you die a broken heart?

Margaret McCartney unpicks recent headlines suggesting its okay not to finish your antibiotics; Lung Cancer screening in the high risk; Can you die a broken heart? Evidence suggests this is a real condition called Takotsubo syndrome and is much more common than previously thought. And gender bias in trials.

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28 minutes

Programme Transcript - Inside Health

Downloaded from www.bbc.co.uk/radio4

 

THE ATTACHED TRANSCRIPT WAS TYPED FROM A RECORDING AND NOT COPIED FROM AN ORIGINAL SCRIPT.  BECAUSE OF THE RISK OF MISHEARING AND THE DIFFICULTY IN SOME CASES OF IDENTIFYING INDIVIDUAL SPEAKERS, THE BBC CANNOT VOUCH FOR ITS COMPLETE ACCURACY.

 

 

INSIDE HEALTH

 

Programme 5.

 

TX:  01.08.17  1530-1600

 

PRESENTER:  MARK PORTER

 

PRODUCER:  ERIKA WRIGHT

 

 

Porter

Coming up today:  Gender bias in clinical trials – what’s good for the gander isn’t necessarily good for the goose.

 

Dying of a broken heart – it’s not just a saying, shock following loss and bereavement really can damage your heart and dangerously so.

 

Clip

I collapsed in the chair, my heart stopped virtually mid-sentence.  Thankfully David’s quick response, commencing CPR, that ultimately saved my life.

 

Porter

And the latest developments in screening for the UK’s biggest cancer killer – lung cancer.

 

But first, antibiotics and recent headlines claiming that new research suggests it’s okay for people to stop taking them once they feel better rather than finishing the course as currently advised.  The media coverage caused quite a bit of confusion and, as ever, the headlines don’t quite reflect the true story, not least that there was no new clinical trial.  Margaret McCartney has been taking a closer look.

 

McCartney

So it wasn’t a new research study, it was a mixture of a semi-review of the literature about what we already know about antibiotic courses plus some opinions by some experts in the area – infection specialist, a microbiologist, a psychologist and a statistician as well.  So all good stuff except the headlines I think really went a bit over the top, there was a bit of shock and awe in the media headlines saying things like:  “Experts say they’re ending complete the course for antibiotics”, “a study says you no longer need to complete the course”, “have you always been asked to finish your antibiotics?  Don’t do so, say the experts”.  And that wasn’t actually really what was said.

 

Porter

And the experts did not say that you should stop the course when you feel better but they said we might be able to use shorter courses and we might be able to stop the course in some people when they feel better.

 

McCartney

Yeah, so what they said was outside hospital where repeated testing may not be feasible patients might be best advised to stop the treatment when they feel better.  In direct contradiction of the World Health Organisation advice.  The problem is the word “might”, I think sometimes that might be okay but sometimes it might not be okay.  And there has been a huge amount of work and perhaps not always the highest quality work and perhaps not always answering the questions we need asked.  But there has been a huge amount of work looking at what the ideal length of an antibiotic course would be.  And of course there’s different reasons why you use antibiotics, sometimes people are using them to get relief from symptoms but other times you’re trying to prevent some kind of damage or risk of harm to the body.

 

Porter

And we are already using fairly short courses, I mean shorter than when I first started practising medicine, I’m thinking of urinary tract infection often three days, chest infections often five days.

 

McCartney

Yeah and that’s right and that’s based on evidence and if you look at the NICE guidelines that’s very much what it says, they have changed over the years.  I started off giving seven day courses for antibiotics, there was a trend for a while to give a single dose of antibiotics but studies came back and said well actually a three day course is best because you get a lot of relapses of symptoms if you just use a one-off course.  So there have been good trials done and there’s still of course lots of questions to answer.  So if you look at the NICE guidance, for example, in treating cellulitis, a skin infection, they say well actually there’s a lack of evidence in the optimum duration.  So there are definitely questions still to be asked.  And in fact the debate about this has been raging for ages.  There’s quite a famous paper that was published in the Lancet in 1999 by a Professor Harold Lambert who was really looking at the same issue and saying actually where’s the evidence that shorter courses of antibiotics cause a problem.  What we need to do is identify areas of uncertainty and for doctors, patients and researchers to get together and work out how best to reduce that uncertainty with high quality trials.

 

Porter

Margaret stay with us.

 

Another story that made the headlines, albeit earlier this year, was a MacMillan initiative in Manchester – screening for lung cancer in supermarket car parks.  Middle aged smokers deemed to be at high risk were invited for screening which included an on-the-spot CT scan if required.  Two and a half thousand people took up the offer, around half of whom had scans.  Forty two cancers were found, most at an early enough stage to be treatable, unlike those tumours picked up on chest X-ray or when symptoms develop, by which time it is often too late. 

 

A finding that adds to growing evidence that screening high risk smokers using CT scans saves lives.  Professor John Field is Chief Investigator for the UK Lung Cancer Screening Trial.

 

Field

The evidence is developing that if you can identify individuals who are at high risk but don’t have symptoms and you find an early cancer there’s a very high chance that one can treat this successfully and they will have a good outcome.  Chest X-rays have many advantages for late stage disease but not for early stage disease.  So therefore the whole clinical move now is to undertake CT scans in individuals, certainly those with symptoms but from a screening point of view a CT scan is much more efficient.

 

Porter

What’s the natural history of most lung cancers in terms of timing, how long might it go from something that’s only visible on CT to something that you might either get symptoms with or would be evident on a normal chest X-ray, are we talking months or years?

 

Field

I think one has to realise that cancers grow at different rates and that some are aggressive and some that actually are quite slow growing.  We would probably look at if you actually take a CT this year and you repeat it in 12 months there will be growth.  And one of the ways that we’ve undertaken is what’s called volumetric analysis.  So you look at the nodule the first time, you calculate the volume, 12 months’ time take another CT and what we work on is 25% increase actually indicates growth.

 

Porter

What proportion of the population that you were screening actually had an abnormality show up, one or more of these nodules show up on the CT scan and what proportion of them did it turn out to be a cancer?

 

Field

First of all I have to tell you what we ran was a trial and therefore the way we undertook the trial is we didn’t just have a yes or no, there was nodule, or no nodule, we actually looked at the size and we took a cut off.  And the cut off that we’re recommending at the moment, if you take diameter, which is easier to talk about, is five millimetres.  Individuals between the five and 9.9 millimetres are considered to be indeterminate or have a suspicious nodule but not actually requiring further work up at that time.  So they require either a three month or a 12 month repeat depending on the size and then at that time looking at the nodule and looking at the volume will determine if they move into the category that is required to be followed up in hospital or clinic.

 

Porter

And what sort of proportion would have had the nodules over five mil?

 

Field

You’re talking around 25% of individuals.

 

Porter

So effectively you’re getting some form of positive result that may be concerning in about one in four people you were scanning?

 

Field

Well it depends what way you look at this and it depends how you describe it to the patient.  You can actually tell the patient that in fact the chance of this developing is actually quite small, knowing the numbers.  However, we do need to keep an eye on it and we believe that the individuals that will gain the most from screening should be offered it.

 

Porter

Well the major benefit, one would presume for the individual you hope, is that you’ve improved their chances of survival.  How sure are we, based on existing evidence, that picking up these cancers at an earlier stage is going to affect their long term survival?

Field

So early stage disease is known to have 70-80% survival over a five year period.  If you compare that to the stage four disease you probably only see 5% living for five years.  So it’s all around identifying early disease and if these individuals are suitable for surgery there’s a very high chance that they will have a good outcome.

 

Porter

Margaret, the evidence that screening reduces deaths from lung cancer is persuasive but it comes at a cost.

 

McCartney

Yeah, so there’s been a few trials now looking at CT scanning in people who are at high risk of developing lung cancer.  So the trials done so far are really trying to target people who are at greatest risk, not of the population more generally.  So people who have been smoking one packet of cigarettes every day for the last 30 years, that kind of level of risk.  And there was a big trial published in the US in 2011 and the headline figure was 15-20% lower death rate from lung cancer with CT screening.  So there was a big headline saying this can make an improvement to deaths from all causes of mortality, so not just lung cancer but also all causes of death, which is relatively unusual in a screening programme and I think has to be taken very seriously because of that.  The other way to look at those figures is that three fewer deaths would occur per thousand people being screened compared with the chest X-ray which was the control group in that big trial.  So the consequence of that is that yes you can reduce death rates, it might be smaller than the initial headlines did appear, but there was also an awful lot of false positives.  These very detailed scans also pick up these lung nodules as well and most of them won’t go on to develop lung cancer, particularly the small ones, but the problem is it can be heard to predict which ones it is.  The first trial that was done found that almost a quarter of people who went through the first round of CT screening had a lung nodule on it and that’s a huge false positive rate.  And the big issue now is trying to work out which ones are the ones that are going to potentially cause you problem and which ones are the ones that can be safely left alone and that’s the really big issue.  And we’ve got a crisis just now in terms of workforce, particularly in radiology, how to read all these scans, get them looked at again, particularly if they’re being repeated and you always have to weigh up what is the cost of doing the test versus what is the benefit.  If you’re creating much more work for not a great deal of benefit for the patient – that’s the really big area now that has to be looked at, how to get the false positive rate down as far as possible to make this a cost effective screening programme because if it is I think it should be looked at seriously just as long as we’re very, very clear what the pros and the cons of it would be.

 

Porter

And Margaret, and just clarify, in terms of cost we’re not just talking resources, it’s about the cost to the individual – I mean being told you’ve got a nodule in your lung is anxiety inducing and we know that that has all sorts of problems potentially.  But presumably the only way eventually to differentiate between some of these suspicious nodules and innocent ones is to go in and do a biopsy and that in itself carries some sort of risk.

 

McCartney

Yeah you’re completely right Mark.  So cost is not just financial, it’s also the cost of knowing that you have something wrong with you or potentially wrong with you, perhaps having invasive tests and investigation and if you’re having a lot of CT scans in the future well the radiation now from these scans is lower than it used to be but it still is there and if you’re a young person having that repeated for a long time that might have an impact as well.  So there’s all kinds of things have to be added into the mix and that’s why I think we really need to be very, very careful when we’re looking at screening programmes and really make sure we’ve got the information that we need in order to make a good judgement about whether or not that’s right for the population and then for individuals in that population to decide whether or not it’s right for them.

 

Porter

Margaret McCartney and Professor John Field.  And there are some links on screening for lung cancer on the Inside Health page of the Radio 4 website.

 

Now we are all familiar with the term “a broken heart” to describe the angst felt following emotional trauma like the loss of a loved one.  However, until recently, few doctors believed broken hearts really existed but they do.  The condition is actually surprisingly common and can be very serious as Valerie Gurk discovered when things started going wrong after her grandson was born.

 

Gurk

It was two years ago and my youngest daughter was having a baby.  After she gave birth to my grandson, when she said – Mum, I don’t feel well – and she blacked out.  The team from the theatre crashed in with a trolley, taken to theatre.  I was probably going into a bit of a shock then…

 

Porter

You felt something was wrong?

 

Gurk

Yeah, it was then I realised I was doubled over and I was having problem breathing.  A nurse said to my husband I should be across the road in Accident and Emergency.

 

Porter

And when you arrived in A&E what did they think had happened to you?

 

Gurk

They did tests, came back and said that I’d had a heart attack.  And at the time I wasn’t thinking about me at all, I was saying to my husband across the road to see how Lindsey was because she was still in theatre.

 

Porter

So at this stage you were still in shock and you didn’t know what was happening to her?

 

Gurk

No, that was the main concern.  It wasn’t until he came back and said – she’s out of theatre, everything’s okay.  I said to him oh by the way you missed the doctor, he came in and said I’d had a heart attack.  Maybe two or three days later a consultant came into the room and said that he was going to refer me because they weren’t sure that’s how this all came about, that it was Takotsubo and I’d never heard of this.

 

Dawson

My name is Dana Dawson, I’m a Reader in Cardiovascular Medicine and a consultant cardiologist at the University of Aberdeen.  People die within a few days of experiencing a strong emotion that makes them feel as if they’ve had a heart attack and that can be a loss of a partner, the loss of a very good friend, many other losses can cause this, for example a financial loss.

 

Porter

Now listeners may be driving along in their car with the radio on saying well I knew that, people die of a broken heart when their spouse dies after 50 years of marriage but have we got hard medical evidence that that’s happening?

 

Dawson

We do now.  Had you asked me this question 15 years ago we would have laughed at each other but now we do have that evidence indeed because we know that these people do not have a heart attack, they think they have a heart attack, the paramedics who come to pick them up think that they’ve got a heart attack.  We, the medical professionals, think they’ve got a heart attack until we gather a bit of evidence with the investigations that we do in the hospital as an emergency and when we see that the heart arteries are clear, are unobstructed but the heart muscle takes a particular shape of an octopus fishing pot, which in Japan is called a Takotsubo, that is when we know that they’ve got a broken heart.

 

Lyon

My name is Dr Alexander Lyon, I’m a consultant cardiologist at the Royal Brompton Hospital and a senior lecturer at Imperial College in London, I have a specialist interest in Takotsubo Syndrome.  Was first described by some Japanese cardiologists in Hiroshima and appeared in a textbook in 1990.  And Hiroshima sits on the opening of an estuary and they have a large fishing port and they felt that the shape of the heart during the Takotsubo attack where the lower portion, the apical portion of the heart, which is the lower tip, is paralysed, whereas the upper part is still contracting.  And it looks like a vase with a narrow neck and a wide bulbous bottom.  And these Japanese cardiologists thought it looked like the local fisherman’s octopus pot, which is known as a Takotsubo in Japanese and that name has lasted the test of time.

 

Porter

What do we think is happening to the heart during these attacks?

 

Lyon

So the heart’s experiencing some major stress, the vast majority of people who experience Takotsubo have either had a background of chronic stress and there’s then a final tipping point.  Or they may be absolutely fine and out of the blue an event happens, either a tragedy like the loss of a loved one or maybe winning the lottery, a high emotional experience, but the linking fact is a huge adrenaline surge.

 

Porter

So this is likely to be emotional?

 

Lyon

It can be physical, sometimes in the context of severe illnesses, severe asthma attacks, allergic attacks where people use epi pens which contain adrenaline as part of the treatment, head injuries.

 

Glass

My name is Ken Glass.  I just got back into playing football after Christmas because I wanted to get fit again.  Roped my mate Dave into coming along.  We were playing football for a couple of hours, I got a knock on the head and suffered a concussion on the back of that.  I got Dave to drive my car to the hospital but within five minutes I collapsed in the chair – my heart stopped virtually mid-sentence.  Thankfully David with his quick response dragging me out of the car and commencing CPR that ultimately saved my life.

 

Lyon

The common thread is a very high surge of adrenaline in the body.  Now we understand from the textbooks and from medical school that adrenaline’s a stimulant, so when we’re playing tennis or running around the heart beats harder and faster.  But our research at Imperial College showed that if you go to the extreme levels of adrenaline actually the muscle starts to shut down and rather than pumping harder and faster it slows down and even paralyses.  And this is what we see in these patients with Takotsubo Syndrome.

 

Porter

And what sort of timescale are we talking about, a typical episode lasts for how long?

 

Lyon

So we see some people who develop immediate chest pain at the time of the emotional stress or event and if they get to hospital very quickly and we follow them through their journey it appears that the heart develops this over about 24-72 hours, so one to three days, before it then starts to get better.  The most severe ones the heart can be paralysed for even a week, 10 days before it really starts to recover.  Approximately four to five people in every 100 don’t survive the acute episode.  There are other ones that come and go pretty instantaneously.

 

Glass

Dave was doing CPR for about 20 minutes until the ambulance arrived.  I was given five shocks from the defib on the ground there and that didn’t work, two more shocks in the back of the ambulance and started my heart again.  Initially they assumed it was a massive heart attack and that’s what they were treating before and it was only after an ultrasonic scan of my heart they were able to see the Takotsubo.  One ventricle ballooned out, not contracting, the way a jellyfish would swim.

 

Dawson

This is probably the strongest mind to body interaction that we have ever seen in medicine.  The heart becomes almost perplexed, it’s almost as if your brain has heard this news and the heart suffers as a consequence and it’s perplexed and it cannot move, it cannot function, in fact it does almost nothing.  It’s quite frightening, even for medical professionals to see that because it’s so acute, it’s so sudden, it’s so dramatic.  And you’ve just seen that the heart arteries are normal and you can’t possibly explain it to yourself for a few moments in your head and then the penny drops – that is a broken heart.

 

Porter

How common is this?

 

Dawson

We thought it was rare.  We thought it was a curiosity that one only sees once in their medical professional career.  It’s not like that at all.

 

Lyon

My understanding of data is that 10% of people who present to hospitals looking like their having a heart attack with severe chest pain, abnormal ECGs, don’t have a coronary blockage.  Of those a fifth have Takotsubo, which works out as about 2% of the total number.

 

Porter

So a lot of these patients are ending up in places where you can get treatment for a heart attack.  Can you get treatment for this syndrome?

 

Lyon

Currently we don’t have any scientifically proven treatments, although experts are starting to tease out what the right things to do are.  Now the natural pattern is the heart generally recovers.  In the severe cases it’s very challenging and one of the reasons is that normally we’d reach for drugs like adrenaline and adrenaline like medications to support a very weak heart in an emergency.  But these medicines will make the situation worse.  So we’re left with using some medications, sometimes we need mechanical support devices, pumping systems that can support the heart.

 

Porter

And what about those who do make an apparent recovery, is there likely to be some long term lingering damage or can they get this again?

 

Lyon

When I see people in the clinic to discuss the future it very much depends on the past and what’s happened to them, have they had previous episodes, was this a one off, what was the trigger.  If the trigger was a unique event in their life it may never happen again.  I tend to quote about 10% of people have a recurrence in the future.  We see that most people who we look after can make a great recovery and do very well.

 

Glass

With regards to my heart there’s no damage, there’s no pathology.  Before leaving hospital they fitted me with a defibrillator.  Sitting there and monitoring my heart regularly.  The assumption is that I’ll just continue to go about my daily business.

 

Porter

Ken Glass.  And in case you are wondering what happened to Valerie Gurk’s daughter and grandson – all turned out well in the end for mother and baby.  There is more information on Takotsubo Syndrome on our website.

 

Now time for the next in our mini-series Inside Clinical Trials in which Margaret McCartney and Carl Heneghan, Professor of Evidence Based Medicine at the University of Oxford, shine a light into the world of clinical research.  This week it’s gender bias and why male orientated trials of medicines and other interventions don’t always reflect the patients they will eventually be used to help.

 

Heneghan

There is a gender gap going back to the start of trials in the ‘60s and ‘70s.  A number of trials, for instance the multiple risk factor intervention trial in 1973 looked at cardiovascular disease risk factors and said we’re going to reduce them in a randomised trial.  That included 12,866 men and no women.

 

Porter

And they were intervening in what way…

 

Heneghan

So they were trying to say – yeah the stuff we say now – we want to learn about lowering cholesterol, lowering blood pressure, reducing smoking, does it improve your outcomes.  You think okay well that’s a bit surprising.  But there were other studies.  National Institute Baltimore Longitudinal Study of Ageing 1958-1975 excluded females despite two thirds of the population being women over 65.  So there was a real issue in the ‘60s, ‘70s and coming into the ‘80s, ‘90s where they did trials solely on men.

 

Porter

But why?

 

Heneghan

I think one reason is you could say there was a gender bias in the researchers, so there was so male factor going on that they thought we’ll just do it in males.  Second, is they thought the population was homogenous so we’ll just pick men and you can apply the results to women.  And then I think third issue is people were really worried about using treatments on women if they were in a fertile age, so they didn’t want to have any risks on the foetus.  So I think them three together sort of created a whole system going forward where we had this gender bias and in areas like cardiovascular disease became absolutely ridiculous.  But the problem is we then learn that actually women are different and that’s not surprising but actually in certain areas they have much worse outcomes.  So for instance lung cancer’s a very good example.  If you look at men and women who smoke the same number of cigarettes women are 20-50% more likely to develop lung cancer.  And it kills more than breast cancer, ovarian and uterine cancers combined.  So we really do need research in some of these areas where we’ve sort of gone down a hole and said we’re just going to look at men because it’s about men and then we can transfer the results.

 

Porter

Margaret, historic – let’s take an example of a medicine, I mean have there been cases where medicines have just been tested on men and it’s assumed that they have the same effect in women?

 

McCartney

Absolutely and what you want to do when you’re doing a clinical trial is to make sure you’re testing your drug on the same population you’re going to be giving that drug to.  And that’s pretty logical but unfortunately has been overlooked time and time again with different population groups.  And one in particular is women.  So we’ve had analysis, for example, of drugs that have been withdrawn from the market in the past in the US where in retrospect they were found to have much greater health risks in women, particularly causing cardiac abnormalities but because they’ve been tested in men these type of rarer side effects hasn’t been picked up.  The FDA in America in the last couple of years has said that women should have a smaller dose of a sleeping tablet – Ambien Zolpidem – because they are more sensitive to the sedative side effects of it.  So I think there definitely are metabolic differences between the male and female body that do need to be taken into account when trials are being run.

 

Heneghan

The one that most surprised me was that the first trial of oestrogen in preventing heart disease was done solely in men.

 

Porter

Oestrogen?

 

Heneghan

Yeah, so that’s a good example.  But one of the other reasons it was reported recently that there is a bias not only in human research but actually in animal research, there’s a selection bias towards males in animal research and that was reported – three quarters of studies only use male animals.  And so they set this bias right at the beginning of the research pipeline.

 

Porter

But modern medicine is about individualised [indistinct word], we’re becoming much more aware that different age groups react differently, different ethnic groups can react differently to medicines, certainly different sexes react differently, is that now being reflected in trials that are going forward?

 

McCartney

Well no.  I mean the elderly population is now the fastest growing population group globally, so we really have to have the research to know how to use medicines safely in this group of people.  But we’ve had the European Medicines Agency on record as saying that exclusion of older people from clinical research and under recruitment to clinical trials is widespread and they concluded that the drugs we are using in older people have not been properly evaluated and that’s a huge problem.  And there’s an organisation now called Predict, the Predict Study, who are looking at trials of very common conditions in the very elderly and are really finding huge under representation of older people and that is a big problem.  And yet we know that trials can be done.  There was a hypertension trial done just in people over 80, that was published in the New England Journal a few years ago, it is possible to do clinical trials in very old people.  But unfortunately they’re not being done in the quantity we need to know that we’re using our medicines safely in this group.

 

Porter

Are women fairly represented these days Carl?

 

Heneghan

Yes, so well the situation’s got better.  In the US the FDA had a report on this, we’ve looked into it.  So the numbers, say, for instance, in cardiovascular disease has come up to about 40% in clinical trials…

 

Porter

Forty percent women?

 

Heneghan

Forty percent women.  However, the problem exists in the reporting because only one third of the trials actually report the male and female differences in the trial report.

 

Porter

Why not?

 

Heneghan

Because I think there’s a complete lack of thought and knowledge coming into the research arena to say actually we understand this really important gender difference and when you think about reporting this you might want to do a systematic review down the line where you want to look at the two or three trials, say what does the effect look like in women and men and what we’re saying is this is just not routinely reported unless there’s a significant problem.

 

Porter

But it must be looked at, one would imagine, I mean these are researchers who are inquisitive by nature.

 

Heneghan

But I think this goes to the whole problem with trial reporting.  What generally tends to happen is people go let’s go for the one big publication, right, get in the big top journal and then down the stream we go well look there are this other data and we haven’t quite got round to analysing these important issues and we’re moving on to the next question.

 

Porter

Carl, in this data from that period, the ‘60s and ‘70s, I mean is that still informing practice today or has that been superseded by more modern representative trials?

 

Heneghan

No I think if you look at the early trials of aspirin done in the 1970s they inform the subsequent systematic reviews…

 

Porter

Done on men.

 

Heneghan

Largely done on men that subsequently informed how we practice.

 

Porter

I obviously meant these data, not this data.  That’s Carl Heneghan and Margaret McCartney.

 

Just time to tell you about next week’s programme, the last in the current series, when we investigate the most important risk factor for breast cancer that you have probably never heard of – dense breasts.  And we visit a school that’s taking part in a pioneering initiative to help future generations be less dependent on pills and doctors. 

 

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